Genetic Investigation of Restricted and Repetitive Behaviors in Autism

Background: Restricted and repetitive behaviors (RRBs) are a defining feature of Autism Spectrum Disorder (ASD). Two RRB subdomains, repetitive sensory motor behaviors (RSMB) and insistence on sameness (IS), have yielded suggestive association in prior genetic studies of ASD. We hypothesize that genetic variants modify the expression of RRBs in individuals with ASD, and that this genetic variation will be associated with RSMB and IS scores.

Objectives:  The primary objective of this study is to search for genetic association to RSMB and IS scores using targeted sequence data.

Methods:  Using the ADI-R, a semi-structured interview for ASD, RSMB and IS scores were calculated in 1118 ASD participants from the Hussman Institute for Human Genomics and the Simons Simplex Collection. All individuals had DNA sequence data available from a 17Mb custom capture covering 681 genes within regions identified by GWAS of ASD. Gene-based and single-variant tests for association with IS and RSMB as quantitative traits were conducted using SKAT-O. Combinations of synonymous, non-synonymous, missense, stop, loss-of-function and splice variants were investigated in different hypothesis tests. A Bonferroni correction for the number of genes tested was used as a significance threshold for each hypothesis with an experiment-wise significance level of 0.05.

Results:  Gene-based tests revealed different genes in association for the respective traits although none passed Bonferroni correction. For the IS trait, two zinc finger genes were most significant when all exonic variants were included (ZNF397 p=2.24E-03, ZSCAN30 p=2.63E-03) and when only missense variants were examined (ZNF397 p=2.73E-03, ZSCAN30 p=3.16E-03). For the RSMB trait, we observed a convergence on the gene PTPRT for analyses of both damaging (p=1.49E-04) and missense (p=1.63E-04) variants. PTPRT (protein tyrosine phosphatase, receptor type, T) is a gene which is highly expressed in the developing and adult CNS and is involved in both CNS signal transduction and cellular adhesion.

Conclusions: These results are in line with prior clinical studies showing IS and RSMB as distinct types of RRBs, potentially supporting this distinction at a biological level. This work is preliminary but suggests that there is value in dissecting the ASD phenotype into measurable traits that can be tested for association to genetic variants.